Primary mediastinal large B-cell lymphoma genomic profiling demonstrates thymic B-cell identity and frequent aberrant somatic hypermutation

Primary mediastinal large B-cell lymphoma (PMBL) is a subtype of non-Hodgkin B-cell lymphoma that most frequently occurs in young adults and is thought to reflect neoplastic transformation of thymic medullary B-cells. We characterized 59 PMBL cases from the Atlas of Blood Cancer Genomes Project. The cohort was predominantly young (median age 35), female (62%), and included individuals from diverse racial backgrounds. Most individuals presented with low-stage disease, favorable ECOG performance status, and high overall survival rate at last follow-up (89%). Whole transcriptome sequencing of 49 PMBL cases revealed gene expression profiles distinct from diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), both activated B cell-like (ABC) and germinal center B cell-like (GCB) cell-of-origin subtypes. PMBLs showed significantly higher expression of thymic B cell-associated genes (p=0.032), supporting their presumed thymic origin. Whole exome and targeted sequencing confirmed recurrent mutations in JAK/STAT, NF-κB signaling, and DNA damage response pathways, with frequent aberrant somatic hypermutation (aSHM) affecting multiple genes. Recurrent copy number alterations included gains at 9p and 12, and losses at 13q. As in prior studies, CIITA rearrangements with diverse partners were recurrent. Although PMBL generally demonstrates excellent outcomes, aSHM-positive cases exhibited inferior progression-free survival (p=0.031), suggesting aSHM as a potential adverse prognostic marker. Our findings further refine the genomic landscape of PMBL and provide new insights into the biology of this neoplasm, with implications for prognostic stratification.